Chemoresistance remains the greatest challenge in improving survival of lung cancer patients. Lung cancer cells have greater expression than normal cells of proteins involved in detoxification of electrophiles and drugs detoxification and efflux pumps [Glutathione and Thioredoxin system and Multidrug resistance proteins] that provides intrinsic resistance against chemotherapy. Studies in project 3 have established that activation of the redox-sensitive transcription factor, Nuclear factor erythroid-2 related factor 2 (NRF2), in response to xenobiotic stress, positively regulates the expression of electrophile, xenobiotic detoxification enzymes and efflux pumps which confer cytoprotection against oxidative stress and apoptosis in normal cells. Kelch-like ECH-associated protein (KEAP1) negatively regulates NRF2 activity by targeting it for proteasomal degradation. Increasing NRF2 activity by small molecule activators might protect the lung epithelium of high risk subjects from oncogenic damage due to carcinogens. However, a surprising finding has emerged in the project that provoked re-thinking about the NRF2 pathway in terms of lung and other cancers. We have recently discovered that dysfunctional KEAP1 activity is a frequent alteration in lung adenocarcinomas which results in greater nuclear accumulation of NRF2 and enhances the transcriptional induction of electrophile, drug detoxification, and efflux proteins. Thus, unlike normal cells, lung cancer cells have unrestrained high NRF2 activity leading to therapeutic resistance. KEAP1 in the adenocarcinomas has deletions, insertions, and missense mutations in functionally important domains of the protein, and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in these cancers is a common event. Mutations were detected in all stages of adenocarcinomas (including stage IA). Decreased KEAP1 activity, in-vitro, causes radio- and Chemoresistance. We have also identified mutations in KEAP1 in prostate tumors and recently similar mutations were reported in breast tumors.The new aims of this proposal are: Specific Aim 1: To determine the association between high NRF2 activity and Chemoresistance in non-squamous non-small cell lung cancer (NSCLC); Specific Aim 2: To determine whether targeted NRF2 inhibition can diminish Chemoresistancein preclinical models; and Specific Aim 3: To determine whether pharmacologically decreasing NRF2 activity in lung cancer can reverse Chemoresistance. Relevance to Public Health: The studies in this project have potential for both identifying biomarkers to predict drug sensitivity in patients with lung adenocarcinomas and to devise new means to reverse Chemoresistance in patients with drug-resistant tumors.